Serine proteases are enzymes which play an important role in the blood coagulation cascade. An important serine protease is factor Xa, which catalyzes the conversion of prothrombin into thrombin. Thrombin is the final serine protease enzyme in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which are cross-linked to form an insoluble gel. In addition, thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in haemostasis and thrombus formation.
In the development of synthetic inhibitors of serine proteases, recently a synthetic NAPAP-pentasaccharide conjugate has been reported as antithrombotic having a dual profile of both direct anti-thrombin activity and ATIII-mediated anti-Xa activity (ATIII: antithrombin III) (Bioorg. Med. Chem. Lett. 1999, 9(14), 2013-8). Although the reported antithrombotic may be an interesting compound, HIT cross reactivity and neutralization by PF4 will be associated with this compound due to the high sulfate content of the pentasaccharide residue (Thromb. Haem. Suppl. 1997, p363 PD1485).